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GWAS-driven Pathway Analyses and Functional Validation Suggest GLIS1 as a Susceptibility Gene for Mitral Valve Prolapse
Mengyao Yu1, Adrien Georges1, Nathan R. Tucker2, Sergiy Kyryachenko1, Patrick T. Ellinor2, David J. Milan2, Russell (Chip) Norris3, Nabila Bouatia-Naji, PhD1.
1INSERM, Paris, France, 2Massachusetts General Hospital, Boston, MA, USA, 3Medical University of South Carolina, Charleston, SC, USA.

Objective- Nonsyndromic Mitral valve prolapse (MVP) is a common degenerative valvular heart disease with severe health consequences, including arrhythmia, heart failure and sudden death.MVP is characterized by excess extracellular matrix secretion and cellular disorganization which leads to bulky valves that are unable to co-apt properly during ventricular systole. However, the triggering mechanisms of this process are mostly unknown. Methods- We applied SRT, i-GSEA4GWAS v2and DEPICT to define pathway enrichment using GWAS summary statistics from ~1,400 cases and ~2,400 controls; UCSC genome browser tool Variant Annotation Integrator (VAI) to annotate SNPs at the GLIS1 locus, and Integrated Genome Browser (IGB) for histone marks and DNase prints. Functional experiments included protein staining for Glis1 in mouse heart during (i) completion of the endothelial-to-mesenchymal transition (EndoMT; embryonic day (E) 13.5), (ii) valve sculpting and elongation (E17.5) and (iii) achievement of the mature adult form (at 9 months) and knockdown using morpholino anti-sense in zebrafish embryos to assess the impact on atrioventricular regurgitation. Results- Using pathway enrichment tools applied to GWAS we show that genes at risk loci are involved in biological functions relevant to cell adhesion and migration during cardiac development and in response to shear stress, and a special enrichment for regulatory genes expressed in the nucleus. Through genetic, in silico and in vivo experiments we demonstrates the role of GLIS1, a transcription factor that regulates Hedgehog signalling that increases the risk of MVP (OR=1.22, P=4.3610-10) and its knockdown causes atrioventricular regurgitation in zebrafish. Conclusions- Our findings define global genetic, molecular and cellular mechanisms underlying common causes of MVP and implicate disrupted endothelial to mesenchymal transition and cell migration. Through the GLIS1association and functional experiments, we describe a new biological pathway under the control of the Hg signalling, as a potential common mechanism to mitral valve degeneration at the population level.


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